Very little is known about thyroid stem/progenitor cells, nor their-specific cell surface markers. We used mice as a model animal to study stem/progenitor cells of thyroid, and partial thyroidectomy as a tool to activate their stem/progenitor cells. This was based on the hypothesis that a sudden loss of thyroid tissue may activate otherwise dormant stem/progenitor cells to participate in thyroid regeneration, a situation that is similar to the well-established partial hepatectomy system in rats and mice. In partial hepatectomy, a part of the liver is removed that allows stem/progenitor cells to become activated and participate in liver regeneration. We first initiated experiments to examine the changes occurred after partial thyroidectomy. We analyzed the thyroid two weeks after partial thyroidectomy, the time when the initial immune response subsided but before the initiation of fibrotic changes. Histological examination of the thyroid indicated the presence of a proliferative center with occasional presence of micro-follicles and BrdU positive cells in the central area of the left or right thyroid lobe regardless of partial thyroidectomy. After partial thyroidectomy, the number of BrdU-positive cells and cells with clear or faintly eosinophilic cytoplasm markedly increased in the central area and the overlapping area close to the cut-edge of the thyroid lobe. Clear cells had scant cytoplasmic components, as determined by electron microscopy, and appeared to be immature cells, some of which retained the characteristic features of C cells, such as the presence of neuroendocrine granules, while others retained follicular cell specific features such as juxtaposition to a lumen and having microvilli at the apical side of the cell. Some of these cells were BrdU-positive, and expressed FOXA2, the definitive endoderm lineage marker. Laser-capture microdissection of cells located in the central areas of the partial thyroidectomized thyroid lobes, followed by microarray and pathway analyses revealed that the genes involved in embryonic development and cancer, among the processes where stem cells are known to play roles, were affected by partial thyroidectomy. The results altogether suggested that cells previously C cells or follicular cells, may be altered after partial thyroidectomy to become immature cells, or immature cells that might be derived from stem/progenitor cells of thyroid, are on their way to differentiate into C cells or follicular cells. These immature cells participate in the repair and/or regeneration of thyroid, a process similar to embryonic thyroid development and/or cancer. This is the first demonstration how thyroid responds to tissue damage such as those caused by partial thyroidectomy, and suggests a possible involvement of thyroid stem/progenitor cells in this process.